Recent advances in our understanding of DNA repair mechanisms have led to the identification of the DNA repair specific nuclease, Artemis. Mutations in this enzyme do not affect viability, but enhance cellular sensitivity to ionizing radiation through the prevention of non-homologous-end-joining (NHEJ)-based DNA repair. Hence, small molecule drugs inhibiting the function of this enzyme are likely to be extremely useful as agents to enhance radiotherapeutic treatment of cancer while sparing normal tissue, thereby not adversely affecting patient quality of life. Importantly, administration of Artemis inhibitory compounds before, during, and after radiotherapy should sensitize tumor cells to radiation damage regardless of mitotic state at the time of treatment, effectively killing slow growing hypoxic tumor cells which are normally resistant to radiotherapy. This phase I application describe studies that will result in the screening of a small molecule library to identify inhibitors of Artemis activity. The subsequent Phase II application will be directed toward development and optimization of lead small molecule candidates that will be tested in-vitro and in-vivo to determine the extent to which these compounds sensitize tumor cells to radiation damage. There are three specific aims for this phase I application: 1) Purify Artemis in sufficient quantities for HTS and optimize screening methods. 2) Screen a approximately 100,000-member small molecule compound library for inhibitors of Artemis. 3) Determine compound specificity toward Artemis and obtain IC50 values for specific compounds.